Anemia

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

[email protected]

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

[email protected]

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

SALT LAKE CITY – Lentiviral delivery of BB305 gene therapy via autologous hematopoietic stem cell transplant (HSCT) was safe and effective for individuals with transfusion dependent beta thalassemia, according to results of a phase 1/2 study.

None of the study participants died, and the majority of patients are now transfusion independent.

The Northstar study is an international, multicenter open-label, single-arm study of adolescents and adults with transfusion dependent beta thalassemia (TDT). A total of 18 patients at a median 21 years of age – 15 young adults aged 18-35 years and three adolescents aged 12-17 years – have now been treated, Mark Walters, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Of these, 11 are now transfusion independent, with most patients stopping transfusions within 6 months of receiving gene therapy, said Dr. Walters, director of the blood and marrow transplantation program at the University of California, San Francisco’s Benioff Children’s Hospital, Oakland.

Eight patients had the beta⁰/beta⁰ genotype, and had essentially been transfusion dependent from infancy. Six other patients were beta^E/beta⁰, and had become transfusion dependent over time. Four patients had other thalassemia genotypes.

Patients who enrolled in the Northstar study first had peripheral stem cell collection via apheresis after mobilization with granulocyte-colony stimulating factor and plerixafor. Then they received myeloablative conditioning with busulfan. At the same time, selected CD34+ cells were tranduced with the BB305 lentiviral vector and cryopreserved. Patients were infused with the transduced cells and managed through the engraftment process.

As a measure of annualized pre-procedure transfusion requirements, patients had received a median 163.6 mL/kg/year of packed red blood cells, Dr. Walters said. Not unexpectedly, liver iron concentration was a median 5.7 mg/g, though with a wide range among participants (0.4-26.4 mg/g). However, participants did not show signs of cardiac tissue iron on T2* magnetic resonance imaging . Six patients had undergone a splenectomy.

The median vector copy number was 0.7 (range, 0.3-1.5), with a median 31.5 CD34+ cells transduced (range, 17.0-58.0). The final cell dose delivered was a median 8.1 x 10⁶ CD34+ cells/kg (range, 5.2-18.1).

“All 18 patients have had at least 18 months of follow-up,” said Dr. Walters, and data from 10 patients has been analyzed out to 2 years. Three patients have a full 3 years of follow-up, he said.

The self-inactivating lentiviral vector has behaved as expected; no replication-competent lentivirus has been found, with investigators conducting assessments at months 3, 6, and 12, and then annually through year 5.

The study protocol also calls for integration site analysis every 6 months for 5 years, and additional analyses at years 7, 10, and 15. Thus far, all samples have shown a polyclonal vector integration profile without clonal dominance, Dr. Walter said.

The median time to neutrophil engraftment was study day 18.5 (range, 14-30), while platelet engraftment was more variable, and overall slower, with engraftment at a median of study day 39.5 (range, 19-191).

Dr. Walters said that he and his colleagues examined characteristics of the four patients who still had platelet counts at or less than 100,000/microliters at 12 months after HSCT. They found that two of these patients had had splenectomies, but saw no clear relationship between speed of platelet engraftment and platelet count at 12 months. Three of the four patients had drug product cell doses less than the median.

However, two patients had no bleeding events after neutrophil engraftment, and bleeding events were all grade 1 or 2 in the other two patients. The slower-than-expected platelet engraftment rate was likely attributable to the ex vivo manipulation of the stem cells, Dr. Walters noted.

Looking at safety data from the point of neutrophil engraftment to the last follow-up, there have been no graft failures; six patients have had serious adverse events. Two events of veno-occlusive disease were assessed as grade 3 and attributed to the transplant. Two of these three patients had an extended hospital stay. Other grade 3 events including intracardiac thrombus, central catheter thrombosis, and cellulitis, as well as hyperglycemia and infectious diseases.

No grade 4 or 5 infections were reported, and the researchers saw no viral reactivations or opportunistic infections.

The safety profile for autologous HSCT with LentiGlobin was overall as expected for a myeloablative regimen that used single-agent busulfan, Dr. Walters said.

Most patients (11/18) with transfusion dependent beta thalassemia were able to stop transfusions, and the remaining patients had reduced transfusion requirements. Participants’ clinical status has stayed consistent through up to 3 years of follow-up, he said.

Of the patients who were able to stop transfusions, just two had the beta⁰/beta⁰ genotype. Among all transfusion independent participants, hemoglobin levels at the last study visit ranged from 8.4-13.7 g/dL. Beta⁰/beta⁰ genotype patients still receiving transfusions have seen a 60% median reduction in transfusion volume and a similar reduction in number of transfusions.

In response to an attendee question, Dr. Walters said that an analysis not included in the presentation has shown a fairly direct relationship between vector copy numbers and transfusion independence.

Currently, he said, vector copy numbers are higher, at around 3. With a higher vector copy number, more CD34+ cells will be transduced and infused, so there may be less concern about the dilutional effect of incomplete myeloablation.

“There may be an opportunity in the future to lessen the intensity of the conditioning regimen,” Dr. Walters said.

The study was funded by bluebird bio. Dr. Walters also reported several consulting relationships with pharmaceutical companies and laboratories.
 

[email protected]

SOURCE: Walters, M et al. 2018 BMT Tandem Meetings, Abstract 62.

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

The European Commission (EC) has extended the approved indication of ferric maltol (Feraccru) to include treatment of all adults with iron deficiency, with or without anemia.

The drug was previously only approved in Europe for the treatment of iron deficiency anemia in adults with inflammatory bowel disease.

The EC’s extended approval governs the marketing of ferric maltol in all 28 European Union member countries, as well as Iceland, Norway, and Liechtenstein.

“We are extremely pleased [the EC] has so rapidly ratified the expansion of the indication for Feraccru,” said Carl Sterritt, chief executive officer of Shield Therapeutics, the company developing the product.

“This decision confirms a significantly broader patient population target opportunity for Feraccru in Europe, where 40 million* people are estimated to be iron deficient.”

Ferric maltol is a stable, non-salt, oral formulation of ferric iron, which has a different mechanism of action than salt-based oral iron therapies.

When salt-based oral iron therapies are ingested, the iron must dissociate from the salt in the gastrointestinal tract to allow the iron to be absorbed and treat the iron deficiency or anemia. This free iron readily chelates to form insoluble clumps as well as producing free radicals that, together, can cause a range of mild-to-severe gastrointestinal adverse events, including nausea, bloating, and constipation.

Conversely, iron can be absorbed from the ferric maltol molecule. As a result, the treatment is less likely to cause gastrointestinal issues. Ferric maltol has been shown in clinical trials (AEGIS 1 and 2) to be well-tolerated by patients who previously failed treatment with salt-based oral iron therapies.

Prior to the extended approval of ferric maltol, the only treatment option for patients with iron deficiency, with or without anemia, who could not tolerate salt-based oral iron therapies, was intravenous iron therapy.

Intravenous iron quickly increases iron stores via direct administration of very large doses of iron, causing an increase in hemoglobin levels that is physiologically controlled and occurs over a period of weeks, as is the case with ferric maltol. However, intravenous iron therapies can be complex to administer and may produce spontaneous hypersensitivity reactions.

*Levi, M et al. Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care. 2016, Eur J Haematol, 97: 583–593. doi:10.1111/ejh.12776

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

Red blood cells

Amgen has withdrawn its application to expand the existing marketing authorization for darbepoetin alfa (Aranesp), according to the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).

The goal with this application was to extend the authorization for darbepoetin alfa to include the treatment of anemia in adults with low-risk or intermediate-1-risk myelodysplastic syndromes (MDS) who have low transfusion demand.

Darbepoetin alfa is currently approved in the European Union (EU) to treat anemia in adults and children with chronic renal failure and adults who are receiving chemotherapy for non-myeloid malignancies.

Amgen withdrew the application for darbepoetin alfa in MDS patients after the CHMP had evaluated initial documentation provided by the company and formulated a list of questions. Amgen had not yet responded to the questions when it notified the CHMP of the withdrawal.

At the time of the withdrawal, the CHMP was of the provisional opinion that darbepoetin alfa could not have been approved for the treatment of anemia in adults with MDS.

This opinion was based on concerns about the data supporting the application—results from the phase 3 ARCADE trial (NCT01362140) and a phase 2 trial (NCT00095264).

The CHMP said changes to the design of the phase 3 trial and the exclusion of a high number of patients from the analysis of the results raise questions about the validity of the data.

In addition, the phase 2 trial, which was conducted in the US, was not in line with EU recommendations for the treatment of MDS patients.

Therefore, at the time of the withdrawal, the CHMP had decided the marketing authorization could not be expanded based on the data provided.

In a letter to the CHMP, Amgen said its decision to withdraw the application is based on the CHMP’s negative opinion.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

stem cell graft

LISBON—Phase 1 results suggest a programmed cellular therapy is safe for use in patients with hematologic malignancies.

The therapy, ProTmune, is being developed as a next-generation allogeneic graft intended to reduce the incidence and severity of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT).

Three of 7 patients who received ProTmune in this trial did develop acute GVHD, and 2 patients died.

However, the remaining 5 patients were still alive and disease-free at last follow-up.

There were no serious adverse events (AEs) attributed to ProTmune. The most common AEs were nausea, vomiting, and chest pain.

These results were presented at the 44th Annual Meeting of the EBMT (abstract A401*).

The trial, known as PROTECT, is sponsored by Fate Therapeutics, the company developing ProTmune.

The phase 1 portion of PROTECT enrolled 7 adults with hematologic malignancies—1 with myelodysplastic syndrome, 3 with acute lymphoblastic leukemia, and 3 with acute myeloid leukemia.

Patients were set to undergo matched, unrelated donor HSCT and received ProTmune as the graft. ProTmune is manufactured by modulating a mobilized peripheral blood graft with 2 small molecules, FT1050 and FT4145.

The patients ranged in age from 34 to 69, and most (n=5) were female. For conditioning, patients received fludarabine/busulfan (n=1), busulfan/cyclophosphamide (n=1), fludarabine/melphalan (n=3), or cyclophosphamide/total body irradiation (n=2).

Results

The data cut-off was February 26, 2018. The median time on study was 228 days (range, 151 to 353).

None of the patients had graft failure. The median time to neutrophil engraftment was 18 days (range, 14 to 22).

Three patients had acute GVHD at day 100 after HSCT. Two patients had grade 2 skin GVHD, and 1 had grade 3 GVHD in the skin and gut.

All 3 patients responded to steroid treatment. GVHD resolved in 5 days for the patient with grade 3 GVHD. For the grade 2 patients, GVHD resolved in 7 days and 8 days, respectively.

None of the patients relapsed, but 2 died—1 of pulmonary edema and 1 of atrial fibrillation.

AEs related to ProTmune included grade 1 vomiting (n=2), grade 2 nausea (n=2), and grade 2 chest pain (n=1).

Phase 2

The phase 2 portion of PROTECT is ongoing. This is a randomized, controlled, double-blinded trial designed to assess the safety and efficacy of ProTmune in up to 60 adults with hematologic malignancies undergoing matched, unrelated donor HSCT following myeloablative conditioning.

Patients are being randomized, in a 1:1 ratio, to receive either ProTmune or a conventional, mobilized peripheral blood cell graft from a matched, unrelated donor.

The primary efficacy endpoint is the cumulative incidence of grade 2-4 acute GVHD by day 100 post-HSCT. Rates of chronic GVHD, cancer relapse, disease-free survival, and overall survival are also being assessed.

*Some data in the abstract differ from the presentation.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.

Photo by Nina Matthews

Pregnant women with severe anemia are twice as likely as those without it to die during or shortly after pregnancy, according to research published in The Lancet Global Health.

Previous studies suggested anemia was strongly associated with death, but this was due to other clinical reasons.

For the current study, researchers took into account factors that influence the development of anemia in pregnancy (such as blood loss or malaria infection) and still found a significant association between anemia and death.

“Anemia in pregnancy is one of the most common medical problems pregnant women encounter, both in low- and high-income countries,” said study author Jahnavi Daru, MBBS, from Queen Mary University of London in the UK.

“We’ve now shown that, if a woman develops severe anemia at any point in her pregnancy or in the 7 days after delivery, she is at a higher risk of dying, making urgent treatment even more important.”

To make this discovery, Dr Daru and her colleagues analyzed World Health Organization data on 312,281 pregnancies in 29 countries* across Latin America, Africa, the Western Pacific region, the Eastern Mediterranean, and South East Asia.

There were 4687 cases of severe anemia (a blood count of less than 70 g/L) and 341 deaths in this group. Deaths were included if they occurred any time after hospital admission until the seventh day post-partum or post-discharge.

The researchers matched 4189 of the women with severe anemia to 8218 women without severe anemia and found a significantly increased risk of death among the women with anemia, both in a crude analysis and an analysis adjusted for potential confounding variables.

In the crude analysis, the odds ratio (OR) for death was 43.35 for women with severe anemia (P<0.0001). In the adjusted analysis, the OR was 2.36 (P<0.0001).

The researchers also conducted a propensity score analysis, matching women with severe anemia to their non-anemic counterparts 1:2. In this analysis, the OR for death was 1.86 (P<0.0001) for the women with severe anemia.

“Anemia is a readily treatable condition, but the existing approaches so far have not been able to tackle the problem,” Dr Daru pointed out. “Clinicians, policy makers, and healthcare professionals should now focus their attention on preventing anemia using a multifaceted approach, not just hoping that iron tablets will solve the problem.”

* The countries included were Afghanistan, Angola, Argentina, Brazil, Cambodia, China, Democratic Republic of the Congo, Ecuador, India, Japan, Jordan, Kenya, Lebanon, Mexico, Mongolia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palestine, Paraguay, Peru, Philippines, Qatar, Sri Lanka, Thailand, Uganda, and Vietnam.

SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.

Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.

SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.

Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.

SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.

Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.

Kari Oakes/Frontline Medical News

[email protected]

SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.

thalassemia

The US Food and Drug Administration (FDA) has granted orphan drug designation to PTG-300, a subcutaneous injectable hepcidin mimetic, for the treatment of beta-thalassemia.

Protagonist Therapeutics, the company developing PTG-300, recently completed a phase 1 trial of the drug.

In this study, healthy volunteers treated with PTG-300 achieved dose-related and sustained reductions in serum iron levels.

In addition, PTG-300 was considered well tolerated, producing no serious adverse events or dose-limiting toxicities.

Protagonist Therapeutics intends to initiate a global clinical trial of PTG-300 in patients with beta-thalassemia following upcoming meetings with the FDA and European Medicines Agency.

“Beta-thalassemia is a rare genetic blood disorder that is characterized by impaired red blood cell production that can result in life-threatening chronic anemia, usually requiring regular and life-long blood transfusions for survival,” said David Y. Liu, PhD, chief scientific officer and head of research and development at Protagonist Therapeutics.

“Over time, these transfusions can lead to excessive iron levels in the body, which can be toxic and consequently lead to end-stage damage to vital organs such as the liver and the heart. As a hepcidin mimetic, PTG-300 is designed to help reduce these excessive iron levels, and, thereby, it may lead to improvements in anemia and decreased need for blood transfusions and chelation therapy.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

thalassemia

The US Food and Drug Administration (FDA) has granted orphan drug designation to PTG-300, a subcutaneous injectable hepcidin mimetic, for the treatment of beta-thalassemia.

Protagonist Therapeutics, the company developing PTG-300, recently completed a phase 1 trial of the drug.

In this study, healthy volunteers treated with PTG-300 achieved dose-related and sustained reductions in serum iron levels.

In addition, PTG-300 was considered well tolerated, producing no serious adverse events or dose-limiting toxicities.

Protagonist Therapeutics intends to initiate a global clinical trial of PTG-300 in patients with beta-thalassemia following upcoming meetings with the FDA and European Medicines Agency.

“Beta-thalassemia is a rare genetic blood disorder that is characterized by impaired red blood cell production that can result in life-threatening chronic anemia, usually requiring regular and life-long blood transfusions for survival,” said David Y. Liu, PhD, chief scientific officer and head of research and development at Protagonist Therapeutics.

“Over time, these transfusions can lead to excessive iron levels in the body, which can be toxic and consequently lead to end-stage damage to vital organs such as the liver and the heart. As a hepcidin mimetic, PTG-300 is designed to help reduce these excessive iron levels, and, thereby, it may lead to improvements in anemia and decreased need for blood transfusions and chelation therapy.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

thalassemia

The US Food and Drug Administration (FDA) has granted orphan drug designation to PTG-300, a subcutaneous injectable hepcidin mimetic, for the treatment of beta-thalassemia.

Protagonist Therapeutics, the company developing PTG-300, recently completed a phase 1 trial of the drug.

In this study, healthy volunteers treated with PTG-300 achieved dose-related and sustained reductions in serum iron levels.

In addition, PTG-300 was considered well tolerated, producing no serious adverse events or dose-limiting toxicities.

Protagonist Therapeutics intends to initiate a global clinical trial of PTG-300 in patients with beta-thalassemia following upcoming meetings with the FDA and European Medicines Agency.

“Beta-thalassemia is a rare genetic blood disorder that is characterized by impaired red blood cell production that can result in life-threatening chronic anemia, usually requiring regular and life-long blood transfusions for survival,” said David Y. Liu, PhD, chief scientific officer and head of research and development at Protagonist Therapeutics.

“Over time, these transfusions can lead to excessive iron levels in the body, which can be toxic and consequently lead to end-stage damage to vital organs such as the liver and the heart. As a hepcidin mimetic, PTG-300 is designed to help reduce these excessive iron levels, and, thereby, it may lead to improvements in anemia and decreased need for blood transfusions and chelation therapy.”

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

[email protected]

SOURCE: Broglie L et al. Abstract 16.

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

[email protected]

SOURCE: Broglie L et al. Abstract 16.

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

[email protected]

SOURCE: Broglie L et al. Abstract 16.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.

Parinda A. Mehta, MD

SALT LAKE CITY—A “risk-adjusted” approach leads to “excellent” survival in patients with Fanconi anemia (FA) undergoing alternative donor hematopoietic stem cell transplant (HSCT), according to a speaker at the 2018 BMT Tandem Meetings.

All FA patients who received personalized doses of busulfan in place of total body irradiation (TBI) were alive and disease-free after undergoing HSCT for bone marrow failure or myelodysplastic syndrome (MDS).

None of the patients developed graft-vs-host disease (GVHD), and the most common toxicity was viral infection.

Parinda A. Mehta, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, presented these results at this year’s BMT Tandem Meetings as abstract 109.*

“We all know that inherent chemotherapy and radiation sensitivity makes transplant for patients with Fanconi anemia quite challenging,” Dr Mehta began. “In our recently published, prospective, multi-institutional study, we showed excellent outcomes of alternative donor transplant in patients with Fanconi anemia without using radiation.”

“In that study,** TBI was replaced by pharmacokinetically adjusted busulfan. It proved that, yes, we can do alternative donor transplant successfully without radiation by showing an overall survival of 80% for a total of 45 patients. We were quite ecstatic to see these numbers.”

The study also showed that younger patients fared better with this regimen, and younger patients did best with the lowest dose of busulfan tested (0.6 mg/kg vs 0.8 to 1.0 mg/kg). In addition, patients who underwent HSCT for bone marrow failure had better outcomes than patients who had MDS.

This led Dr Mehta and her colleagues to hypothesize that adjusting busulfan dosing based on a patient’s age and disease status at HSCT could minimize toxicity and improve outcomes.

Patients

The researchers tested their theory in 22 FA patients. They had a median age of 7 (range, 4-27), and most (n=13) were female.

Twelve patients had pancytopenia, 6 had severe single-lineage cytopenia, 3 had low-grade MDS, and 1 patient had acute myeloid leukemia (AML).

Eighteen patients had a history of transfusions, and 3 had a history of androgen use.

Treatment

The preparative regimen consisted of 4 doses of busulfan (every 12 hours on day -7 to -6), followed by cyclophosphamide at 10 mg/kg/day (on day -5 to -2), fludarabine at 35 mg/m²/day (on day -5 to -2), and rabbit antithymocyte globulin at 2.5 mg/kg/day (on day -5 to -2).

Busulfan doses were adjusted according to age and disease status.

Children (age 18 and younger) with bone marrow failure received busulfan at 0.6 to 0.8 mg/kg. Children with MDS/AML received busulfan at 0.8 to 1.0 mg/kg. Adults (19 and older) received the lowest dose of busulfan—0.4 mg/kg—regardless of disease status.

“At the first sight, this will look counterintuitive . . . ,” Dr Mehta said. “However, based on our previous experience, in general and also from results of our previous study, this was specifically designed to avoid upfront TRM [transplant-related mortality] for these adult patients.”

All 22 patients received CD34-selected, T-cell-depleted peripheral blood stem cells from unrelated donors. Eleven patients received a fully matched graft (10/10), 8 patients had a 9/10 match, and 3 had an 8/10 match.

The median number of CD34+ cells/kg was 23.9 x 10⁶ (range, 4.9-76.6), and the median number of CD3 cells/kg was 1 x 10⁴ (range, 0.003-3.1).

T-cell depletion was the only GVHD prophylaxis used.

Patients with MDS/AML could receive azacitidine at day 42 after HSCT, an option intended to prevent relapse in these patients.

Toxicity

There were no cases of acute or chronic GVHD.

Toxicities included infections (n=24), oral mucositis (n=14), hyperbilirubinemia (n=2), pulmonary hemorrhage (n=1), and sinusoidal obstruction syndrome (n=1).

There were 20 viral infections, 4 bacterial infections, and no fungal infections. Viral infections included BK virus (n=7), cytomegalovirus (n=6), Epstein-Barr virus (n=6), and adenovirus (n=1).

Dr Mehta noted that viral infections are “not unexpected in a T-cell-depleted graft setting.”

“Because we know this complication [can occur], and we worry about our patients, one of the things that, in recent years, we have done is, we manufacture viral-specific CTLs [cytotoxic T lymphocytes] for all of these patients ahead of time whenever possible,” she said.

“To give you an example, 19 out of these 20 patients’ viral infections—or rather, viremias—are completely under control with the use of either antivirals or donor-specific CTLs, including a third-party CTL in one of the patients.”

Response and survival

All 22 patients engrafted. The median time to neutrophil engraftment was 9 days (range, 8-10), and the median time to platelet engraftment was 16 days (range, 11-40).

Twenty-one of the 22 patients (95%) were alive and disease-free at last follow-up. The median follow-up was 21 months (range, 6-44).

The single AML patient achieved remission but died of post-transplant lymphoproliferative disorder (PTLD) on day 202 after HSCT. Dr Mehta said this was due to partial loss of follow-up and noncompliance with medical recommendations during PTLD treatment.

The AML patient also had “significant upfront toxicity” but “recovered very nicely,” according to Dr Mehta. He had severe mucositis, herpetic stomatitis, and sinusoidal obstruction syndrome that responded to defibrotide.

“Overall, we are quite excited to see 95% overall survival for this cohort and conclude that the current risk-adjusted approach leads to excellent overall survival and disease-free survival in patients undergoing alternative donor transplant either for marrow failure or MDS/AML,” Dr Mehta said.

“Enrollment is ongoing, and we hope to see continued success in patients with MDS/AML as well as in adult patients.”

*Data in the abstract differ from the presentation.

**Mehta PA et al. Radiation-free, alternative donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; doi: https://doi.org/10.1182/blood-2016-09-743112.